Alzheimer's disease (referred as “AD” hereinafter) is a debilitating neurodegenerative disorder in the elederly effecting millions of individuals throughout the world. One of the pathological hallmarks of AD is the extracellular protein deposits referred as senile plaques (Geula, C. et al., Nat. Med., 4, 827–831 (1998)) that consist predominantly of an aggregated peptide known as β amyloid (referred as “Aβ” hereinafter). Aβ, 39–43 amino acid peptides, is produced through proteolytic processing of the β amyloid precursor protein (referred as “βAPP” hereinafter) by β-secretase and γ-secretase (Glenner, G. G. et al., Biochim. Biophys. Res. Commun., 120, 885–890 (1984); Yasojima, K. et al., Neurosci. Lett., 12, 97–100 (2001)). This peptide is particularly amyloidogenic and appears to form the core of the neuritic plaques. The number of plaques appears to correlate with the degree or severity of the dementia (Hasse, C. et al., Cell, 75, 1039–1042 (1993); Selkoe, D. J., J. Neuropathol. Exp. Neurol., 53, 438–447 (1994)). In addition, fibrillar Aβ, amorphous aggregates of Aβ, has been reported to cause neuronal cell death in primary rat hippocampal cultures whereas soluble monomeric species of Aβ are relatively less toxic than fibrillar Aβ (Yankner, B. A. et al., Science, 250, 279–282 (1990)). Other studies suggested that prefibrillar aggregates of Aβ are neurotoxic (Zhu, Y. J. et al., FASEB J., 14, 1244–1254 (2000)). Mutations in genes of either APP or presenilins (PS), which seemed to have a γ-secretase activity, may lead to elevation of the production of Aβ, and are associated with severe and early-onset forms of AD (Yoshiike, Y. et al., J. Biol. Chem., 276, 32293–32299 (2001)).
Taken together, Aβ aggregation is considered as a crucial event in the pathogenesis of AD. Accordingly, the efficient inhibition of Aβ aggregation is considered as a powerful way to prevent or treat AD. Therefore, extensive studies have been carried out to discover anti-amyloidogenic compounds from natural or synthetic sources.
Several low molecular weight compounds such as antioxidants, free radical scavengers, cholesterol lowering drugs, calcium channel blockers, and γ-secretase inhibitors have been developed as a therapeutic agent for AD (Selkoe, D. J., Physiol. Res., 81, 741–766 (2001)). Among these compounds, γ-secretase inhibitors are known to decrease Aβ production 30–40% (Schroeter, E. H. et al., Nature., 393, 382–386 (1989); Vandermeeren, M. et al., Neurosci Lett., 27, 145–148 (2001)). Among high molecular weight compounds, anti-Aβ antibody, a macromolecular protein, is a good example to enhance clearing of Aβ deposits in transgenic mice that already had begun to develop plaques, possibly by the recruitment of local microglia (Schenk, D. et al., Nature, 400, 173–177 (1999)). Recently, neprilysin which is also known as enkephalinase as well as the common acute lymphoblastic leukemia antigen (CALLA) has been confirmed to be involved in degradation of Aβ-amyloid by its proteolytic activity (Iwata, N. et al., Nat Med., 6, 718–719 (2000); Iwata, N. et al., Science, 292, 1550-1552 (2001)). Moreover, reduced neprilysin level in the plaque area of AD brain was found, suggesting that reduced degradation of Aβ caused by low levels of neprilysin may contribute to AD pathogenesis (Yasojima, K. et al., Neurosci Lett., 12, 97–100 (2001)). In addition, Eckman et al. reported recently that endothelin-converting enzyme-1 (ECE-1) degraded Aβ in vitro at multiple sites (Eckman, E. A. et al., J. Biol. Chem. 27, 24540–24548 (2001)). These results demonstrate that the endogenous concentration of Aβ peptides is regulated not only by its production but also by its catabolism with a specific proteolytic peptidase. Nevertheless, there is something yet to learn about not only high molecular weight compounds inhibiting neurotoxicity caused by Aβ peptide but also a therapeutic agent for neurodegenerative disorders using a high molecular weight biomolecule without side effects by low molecular weight.
Thus, the present inventors separated a Streptomyces sp. strain as a target strain producing an active protein inhibiting the aggregation of Aβ peptide inducing AD, and completed this invention by verifying that a protein separated from the strain could be used as a therapeutic agent for neurodegenerative disorders.